3225 Dasatinib Dose-Optimization in Chronic Phase Chronic Myeloid Leukemia (CML-CP): Two-Year
Data from CA180-034 Show Equivalent Long-Term Efficacy and Improved Safety with 100 Mg Once
Daily Dose
Monday, December 8, 2008
Hall A (Moscone Center)
Neil P. Shah, MD, PhD1, Dong-Wook Kim, MD, PhD2*, Hagop M. Kantarjian, MD3, Philippe Rousselot, MD,
PhD4*, Pedro Dorlhiac-Llacer5*, Jorge Milone, MD6*, Martin C Müller, MD7*, Yousif Matloub8*, Alexandre
Lambert9* and Andreas Hochhaus, MD7
1Hematology/Oncology, University of California, San Francisco, San Francisco, CA
2Division of Hematology, St. Mary's Hospital, Seoul, South Korea
3M.D. Anderson Cancer Center, Houston, TX
4Hôpital Mignot and CIC9504, Versaille, France
5Hematology, Hospial das Clínicas da Universidade de São Paulo, São Paulo, Brazil
6Instituto de Trasplante de Medula Osea, Buenos Aires, Argentina
7Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany
8Bristol-Myers Squibb, Wallingford, CT
9Bristol-Myers Squibb, Braine-l'Alleud, Belgium
Dasatinib (SPRYCEL®) is an effective BCR-ABL inhibitor and is 325-fold more potent than imatinib in vitro
against unmutated BCR-ABL. CA180-034 is a randomized, phase III, open-label study in patients with CML-CP
(N=670) who have resistance, suboptimal response, or intolerance to prior imatinib 400–800 mg/d. Patients
were randomized using a 2x2 factorial design to one of four treatment arms: 100 mg once daily (QD), 70 mg
twice daily (BID), 140 mg QD, or 50 mg BID. Time to and duration of response, progression-free survival (PFS),
and overall survival (OS) were estimated using Kaplan-Meier analysis. Earlier reports demonstrated that
dasatinib 100 mg QD (the currently approved dose in CML-CP) maintains efficacy while significantly minimizing
adverse events (AEs). This finding was supported by pharmacokinetic analyses, which have demonstrated a
correlation between low dasatinib steady-state trough plasma concentration (achieved with 100 mg QD dosing)
and less frequent key toxicities and fewer dose interruptions. With a minimum of 2 years of follow-up in all
patients, dasatinib 100 mg QD treatment resulted in a MCyR rate of 63% and a CCyR rate of 50%, and rates
were similar in the other 3 arms (MCyR: 61%–63%; CCyR 50%–54%) (Table). Rates were similar when 14
patients with Ph-negative BCR-ABL-positive disease were excluded. Among responding patients in the 100 mg
QD arm, median time to MCyR was 12.4 weeks and to CCyR was 13.0 weeks, and after 24 months, 87% of
patients had maintained their MCyR and 89% had maintained their CCyR, with similar results in other arms. The
24-month PFS rate with 100 mg QD was 80% (vs 75%–76% in other arms) and OS rate was 91% (vs 88%
–94%). In all arms, high response rates were achieved in patients with or without a baseline BCR-ABL mutation
(CCyR rates for 100 mg QD: 40% vs 54%, respectively). Dasatinib was well tolerated and the incidence of
treatment-related AEs after a minimum of 2 years of follow-up was similar to rates after a minimum of 1 year. In
the 100 mg QD arm, overall 2-year rates (vs 1 year) were 2% (vs 2%) for grade 3 pleural effusion (grade 4:
0%), 23% (vs 22%) for grade 3/4 thrombocytopenia, and 35% (vs 34%) for grade 3/4 neutropenia. Among the 4
treatment arms, significant differences were observed in the overall incidences of drug-related pleural effusions
(all grades: p=0.049) and cytopenias (p=0.003 for grade 3/4 thrombocytopenia), with lowest rates observed for
100 mg QD. After a minimum of 2 years of 100 mg QD treatment, 12% of patients discontinued therapy following
drug toxicity (vs 6% after 1 year), compared with 2-year rates of 16%–21% in other arms. Overall, 2-year data
from CA180-034 extend previous findings and demonstrate that dasatinib dose optimization at 100 mg QD is
associated with minimal incidence of key grade 3/4 toxicities in Year 2, and maintains long-term efficacy, in
patients with CML-CP following resistance, suboptimal response, or intolerance to prior imatinib. Response
duration and PFS with dasatinib 100 mg QD are similar to other dose schedules.
Table
100 mg QD
70 mg BID
140 mg QD
50 mg BID
All randomized patients
n=167
n=168
n=167
n=168
CHR (%)
92
88
87
92
MCyR (%)
63
61
63
61
Median time to MCyR (wks)
12.4
12.3
12.3
12.3
MCyR maintained at 24 mos (%)
87
88
68
88
CCyR (%)
50
54
50
50
Median time to CCyR (wks)
13.0
12.9
13.8
12.9
CCyR maintained at 24 mos (%)
89
85
78
93
24-month PFS (%)
80
76
75
76
24-month OS (%)
91
88
94
90
Excluding Ph(–) BCR-ABL(+)
n=164
n=163
n=163
n=166
MCyR (%)
63
61
63
61
CCyR (%)
49
53
50
50
All treated patients
n=165
n=167
n=163
n=167
Pleural effusion (drug-related), grade 3/4 (%)
2
5
5
4
Neutropenia, grade 3/4 (%)
35
45
44
47
Thrombocytopenia, grade 3/4 (%)
23
38
41
36
Dose interruption (%)
62
77
79
72
Dose reduction (%)
39
62
62
46
1095 Dasatinib-Associated Major Molecular Responses Are Rapidly Achieved in Patients with
Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Following Resistance, Suboptimal Response,
or Intolerance on Imatinib
Saturday, December 6, 2008
Hall A (Moscone Center)
Andreas Hochhaus, MD1, Martin C Müller, MD1*, Jerald Radich, MD2, Susan Branford3, Benjamin Hanfstein,
MD1*, Philippe Rousselot, MD, PhD4*, Jeffrey H Lipton, MD, PhD5, Eric Bleickardt6*, Ritwik Sinha6* and Timothy
P Hughes, MD3*
1III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany
2Fred Hutchinson Cancer Rsch. Ctr., Seattle, WA
3Institute of Medical and Veterinary Science, Adelaide, Australia
4Hôpital Mignot and CIC9504, Versaille, France
5Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada
6Bristol-Myers Squibb, Wallingford, CT
Dasatinib (SPRYCEL®) is a highly potent BCR-ABL inhibitor, with 325-fold higher potency than imatinib and a
16-fold higher potency than nilotinib in vitro. Across a series of phase II and III trials with more than 2 years of
follow-up, dasatinib has demonstrated durable efficacy in patients with CML following resistance, suboptimal
response, or intolerance to imatinib. Qualitative and quantitative assessment of BCR-ABL transcripts by RT-
PCR is the most sensitive method for assessing minimal residual disease in patients with CML. In the treatment
of patients with CML in the first-line setting, achievement of a major molecular response (MMR) within 18 months
of therapy is considered to be clinically important. Here, molecular responses to dasatinib in patients with CML-
CP following resistance, suboptimal response, or intolerance to imatinib were analyzed using data from two
phase II studies (CA180-013 [START-C], -017 [START-R]) and a phase III dose-optimization study (CA180-
034). BCR-ABL mRNA levels were determined in peripheral blood samples using real-time quantitative PCR and
results were standardized using the international scale. A MMR was defined as a reduction of BCR-ABL
transcripts to ≤0.1%. Samples were assayed at one of four laboratories (Mannheim, Germany; Adelaide,
Australia; or Seattle, USA for -013 and -017; and Wallingford, USA for -034). Of 1,158 patients with CML-CP
who were randomized to (017) or treated with (013/034) dasatinib, 1,067 had a molecular assessment and were
included in the analysis. After 3, 6, 12, and 24 months of follow-up, a MMR was achieved by 12%, 22%, 35%,
and 40%, respectively, of all patients analyzed. The 24-month MMR rate among patients who had achieved or
maintained a complete cytogenetic response was 72%. In patients with imatinib resistance/suboptimal response
(n=829), overall MMR rates after 3, 6, 12, and 24 months were 10%, 18%, 29%, and 34%, respectively, and in
patients with imatinib intolerance (n=238), MMR rates were 22%, 37%, 55%, and 63%, respectively. In patients
treated during the 034 study with dasatinib 100 mg once daily, which is associated with fewer key side effects,
MMR rates at different time points were similar to rates with other dose schedules (24-month MMR: 100 mg QD,
36%; other schedules, 38%). Among all patients who achieved a MMR, median time to MMR was 5.7 months
(6.0 months with 100 mg QD), and after 18 months, 92% of responding patients were without loss of MMR (88%
with 100 mg QD). Overall, the results of this analysis demonstrate that high rates of MMR are rapidly achieved
in patients with CML-CP treated with dasatinib following resistance, suboptimal response, or intolerance to
imatinib.
Table
Major molecular response (%)
Follow-up (months)
3
6
12
24
All analyzed patients (n=1067)
12
22
35
40
Resistant/suboptimal response (n=829)
10
18
29
34
Intolerant (n=238)
22
37
55
63
Phase II studies (013/017) (n=467)
17
27
39
44
Resistant (n=373)
13
21
31
35
Intolerant (n=94)
33
50
69
78
Phase III dose-optimization study (034) (n=600)
9
19
32
38
Resistant/suboptimal response (n=456)
7
16
27
33
Intolerant (n=144)
15
29
46
54
Response by dose schedule
100 mg QD (n=154)
7
18
29
36
70 mg BID (n=146)
9
18
32
38
140 mg QD (n=144)
13
22
32
38
50 mg BID (n=156)
7
17
34
38
450 Dasatinib Time to and Durability of Major and Complete Cytogenetic Response (MCyR and CCyR)
in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)
Monday, December 8, 2008: 2:45 PM
2009-2011-2022-2024 - West (Moscone Center)
Michele Baccarani, MD1, Gianantonio Rosti1*, Giuseppe Saglio, MD2*, Jorge Cortes3*, Richard Stone4*,
Dietger W. Niederwieser, MD5, Eric Bleickardt6*, Ritwik Sinha6* and Bengt Simonsson7
1'L. and A. Seragnoli', Istituto di Ematologia e, Bologna, Italy
2Department of Clinical and Biological Sciences, University of Turin, Orbassano,Turin, Italy
3The University of Texas MD Anderson Cancer Center, Houston, TX
4Dana Farber Cancer Institute, Boston, MA
5Abteilung Hamatologie/Onkologie, Universitat Leipzig, Leipzig, Germany
6Bristol-Myers Squibb, Wallingford, CT
7Department of Hematology, University Hospital, Uppsala, Sweden
Dasatinib (SPRYCEL®) is a potent BCR-ABL inhibitor that is 325-fold more potent than imatinib and 16-fold
more potent than nilotinib in vitro against unmutated BCR-ABL. In this analysis, time to, duration, and rates of
cytogenetic responses to dasatinib were determined using Kaplan-Meier analysis in patients recruited to phase
II trials in imatinib-resistant or -intolerant CML-CP (START-C and -R), which have more than 2 years of follow-
up. In both trials, patients received dasatinib at the previous dose of 70 mg twice daily (the approved dose in
CML-CP is now 100 mg once daily following phase III dose optimization demonstrating improved tolerability). In
START-C, imatinib-resistant and -intolerant patients were recruited, and separate analyses were performed for
each group. In START-R, a randomized trial of dasatinib vs escalated-dose imatinib, only imatinib-resistant
patients were recruited and patients from the dasatinib arm were analyzed prior to cross over. In all dasatinib
trials, MCyRs and CCyRs were determined using conventional bone marrow cytogenetic assessment.
Progression was defined as increasing white blood cell count, loss of complete hematologic response, loss of
MCyR, transformation to accelerated or blast phase, or death. Among imatinib-resistant patients treated in
START-C, a MCyR had been achieved at 3, 6, and 12 months by 29%, 40%, and 51%, and a CCyR had been
achieved by 18%, 28%, and 39%, respectively (Table). At 24 months, MCyR and CCyR had been achieved by
55% and 44%, respectively. Among responding patients, median time to MCyR was 2.9 months and to CCyR
was 5.5 months. In resistant patients who had achieved a MCyR, 94% and 84% had maintained this response
12 and 24 months after it had been initially achieved. For CCyR, 95% and 86% had maintained their response
at 12 and 24 months, respectively. Progression-free survival (PFS) at 12 and 24 months for imatinib-resistant
patients was 88% and 75%. In START-R, dasatinib response rates and durability were similar to those observed
in the imatinib-resistant population of START-C, and median times to MCyR and CCyR were 2.8 and 4.1
months, respectively. Among imatinib-intolerant patients treated in START-C, MCyRs had been achieved at 3,
6, and 12 months by 62%, 74%, and 80%, and CCyRs by 44%, 65%, and 74%, respectively. Rates at 24
months had reached 82% for MCyR and 78% for CCyR. Median times to achieve MCyR and CCyR in the
intolerant population were both 2.8 months. Among responding patients, 99% and 97% of intolerant patients
were without loss of MCyR 12 and 24 months after responding, and 100% and 98% were without loss of CCyR,
respectively. The 12- and 24-month PFS rates were 98% and 94%. In conclusion, dasatinib treatment results in
high rates of durable MCyRs and CCyRs in patients with imatinib-resistant or -intolerant CML-CP, and
responses are achieved rapidly in most patients.
Table
START-C
START-R
Overall
(N=387)
Resistant
(n=288)
Intolerant
(n=99)
Resistant
(n=101)
CCyR achieved (%)
3 months
25
18
44
22
6 months
37
28
65
29
9 months
44
34
73
35
12 months
48
39
74
37
18 months
51
42
78
43
24 months
53
44
78
44
Median time to CCyR (months)
3.2
5.5
2.8
4.1
Patients without loss of CCyR (%)
12 months
97
95
100
97
24 months
90
86
98
94
PFS (%)
12 months
91
88
98
91
24 months
80
75
94
86
182 Efficacy of Dasatinib in Patients (pts) with Previously Untreated Chronic Myelogenous Leukemia
(CML) in Early Chronic Phase (CML-CP)
Monday, December 8, 2008: 7:15 AM
Halls B and C (Moscone Center)
Jorge Cortes, Susan O'Brien*, Gautam Borthakur*, Dan Jones*, Farhad Ravandi*, Charles Koller*, Ofelia
Mesina*, Alessandra Ferrajoli*, Jianqin Shan* and Hagop Kantarjian*
M.D. Anderson Cancer Center, Houston, TX
Background: Dasatinib (BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC with significant
activity in pts with CML-CP resistant to or intolerant of imatinib (IM). We initiated a phase II trial to study efficacy
and safety of dasatinib in pts with previously untreated CML-CP. Aims: To investigate the efficacy and safety of
dasatinib as initial therapy for patients with CML-CP. Methods: The primary objective was to estimate the
proportion of pts attaining major molecular response (MMR) at 12 months (mo). Pts with previously untreated
CML-CP were eligible and received dasatinib 100 mg/day, randomized to either 50 mg-twice-daily (BID) or a 100
mg-once-daily (QD). Results: Fifty pts have been enrolled (25 on the QD schedule, 25 BID). Median age was 45
years (yrs) (range 18–76 yrs); 75% are Sokal low risk. Median follow-up is 24 months (mo). Overall, 44/45
(98%) evaluable patients achieved complete cytogenetic response [CCyR]. The CCyR rate at 3, 6 and 12 mo
compares favorably to that observed in historical controls treated with imatinib 400mg or 800 mg daily:
Mo on therapy
Percent with CCyR (No. evaluable)
P value
Dasatinib
Imatinib 400mg
Imatinib 800mg
3
78 (45)
37 (49)
62 (202)
0.0003
6
93 (41)
54 (48)
82 (199)
<0.0001
12
97 (35)
65 (48)
86 (197)
0.0001
18
88 (33)
68 (38)
89 (179)
0.004
24
80 (25)
70 (40)
88 (173)
0.006
MMR was achieved in 12/35 (34%) at 12 mo and 12/25 (48%) at 18 mo. One of 46 (2%) evaluable pts have
achieved confirmed complete molecular response, and 1 other unconfirmed (ie, only achieved on their last
assessment). Grade 3-4 non-hematologic toxicity (regardless of causality) included pruritus (13%), fatigue (6%),
neuropathy (4%), and memory impairment (4%). Pleural effusion occurred in 21% evaluable pts (grade 3-4 in
2%). Grade 3-4 hematologic toxicity (transient) was thrombocytopenia in 11%, neutropenia in 21%, and anemia
in 9%. Twenty-seven (54%) pts required transient treatment interruption. The actual median daily dose for all
pts was 100mg. There is no significant difference in grade 3-4 toxicity by treatment schedule. Four pts came off
study: 1 pts choice after 1 dose, 1 for toxicity (pleural effusion, QD schedule), and 2 lost response after multiple
treatment interruptions (1 myelosuppression, 1 pleural effusion, both BID schedule). Two other pts have lost
response because of non-compliance. 24 month EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off
because of toxicity) is 81%. Conclusion: Rapid CCyR occurs in most patients with previously untreated CML-CP
treated with dasatinib frontline therapy with a favorable toxicity profile. Accrual to this trial continues.
3230 Pregnancy Outcomes among Patients with Chronic Myeloid Leukemia Treated with Dasatinib
Monday, December 8, 2008
Hall A (Moscone Center)
Poster Board III-312
Jorge Cortes, MD1, Susan O'Brien1*, Patricia Ault1*, Gautam Borthakur1*, Elias Jabbour1*, Brigid Bradley-
Garelik2*, Krisztina Debreczeni3*, Daniel Yang2*, David Liu2* and Hagop Kantarjian1*
1M.D. Anderson Cancer Center, Houston, TX
2Bristol-Myers Squibb, Wallingford, CT
3Bristol-Myers Squibb, Pennington, NJ
Dasatinib has been shown in non-clinical studies to cause fetal toxicities in animals, but the effect of exposure
during conception and pregnancy in humans is not known. Despite the requirement for contraception while on
therapy with dasatinib, occasional pregnancies have been reported. The current study and post-marketing data
report the outcomes of pregnancies occurring among 16 patients (8 females and 8 males) who received
dasatinib therapy. Among the 8 female patients found to be pregnant while on dasatinib therapy, induced
abortion was reported in 3 cases: 2 due to patient decision and 1 for unknown reasons. Two cases of
spontaneous abortion were reported. The first was at 8 weeks gestation in a 38-year-old patient (G1P1) with a
history of tobacco use. Birth defects of the fetus were not reported; though it is unknown if an autopsy was
performed. The other spontaneous abortion was reported at 9 weeks gestation in a 33-year-old patient (G3P3)
taking dasatinib for over 2 years. The medical history of this patient includes tobacco and alcohol use. Of the 3
deliveries, one patient had a normal healthy infant. The second patient (age: 29 years, G2P2) delivered a
healthy infant by Caesarean section at 7 months gestation (reason for Caesarean section unknown). This
patient received dasatinib 140mg/day for approximately 4 months, but was ‘lost to follow up' for 2 months and
study drug compliance was unknown. Upon her return, the patient had a positive pregnancy test with an
estimated gestation of 4 weeks. The infant was reported as ‘small for date' but without obvious birth defects.
Apgar scores were also unknown for this infant. In the final case, a patient on dasatinib 100mg/day for
approximately 5 months was identified as pregnant (G0P0) at 21 weeks of gestation. The estimated delivery
date has not yet occurred at the time of writing, but the pregnancy course has been normal. Among 8 male
patients treated with dasatinib with partners becoming pregnant while on treatment, normal newborns were
reported for 7 cases, with the outcome of the other case unknown. All male patients remained on treatment
during and after the pregnancies. In 1 case, the mother experienced pre-eclampsia but delivered a healthy
newborn at 37 weeks, without birth defects or neonatal complications. In summary, although the limited data
reported in this study did not show evidence that dasatinib treatment has a negative impact on pregnancy (for
the mother or fetus), patients receiving dasatinib should be advised to practice adequate contraception.
Table 1. Outcome of Female Patients Electing to Carry Pregnancy
Duration of Fetal Exposure to Dasatinib
Fetal Outcome
Maternal Outcome
Dasatinib Dose*
Duration of Dasatinib Therapy
Pt D
5 weeks
8wk spontaneous
abortion
no adverse reaction reported
180 mg/day
approximately 9.5 months
Pt E
9 weeks
9wk spontaneous abortion
no adverse reaction reported
100 mg BID
30 months
Pt F
7 weeks
normal healthy
no adverse reaction reported
140 mg / day
approximately 15 months
Pt G
unknown
"small for date" – healthy newborn
C-section at 7 months
140mg / day
approximately 4 months
Pt H
21 days
to be determined
100mg / day
5 months
*at time of onset
3241 Dasatinib in Children and Adolescents with Relapsed or Refractory Leukemia: Interim Results
of the CA180-018 Phase I Study from the ITCC Consortium
Monday, December 8, 2008
Hall A (Moscone Center)
Poster Board III-323
C. Michel Zwaan, MD, PhD1, Carmelo Rizzari2*, Vincent H.J. van der Velden3*, Berna Beverloo4*, M. L. den
Boer5, Andre Baruchel6, Francoise Mechinaud7*, Donna Lancaster8*, Yousif Matloub9*, Dominique
Derreumaux10*, Rob Pieters11 and Pamela Kearns12*
1Department of Pediatric Hematology/Oncology, Erasmus MC Rotterdam-Sophia Children's Hospital,
Rotterdam, Netherlands
2University of Milano - Bicocca, Monza, Italy
3Department of Immunology, Erasmus MC, Rotterdam, Netherlands
4Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands
5Department of Pediatric Oncology, Erasmus MC, Rotterdam, Netherlands
6Department of Pediatric Hematology, Hopital St-Louis, Paris, France
7Department of Hematology, CHU Hotel-Dieu, Nantes, France
8School of Cancer Nursing and Rehabilitation, The Royal Marsden NHS, United Kingdom
9Bristol-Myers Squibb, Wallingford, CT
10Bristol-Myers Squibb, Braine L'Alleud, Belgium
11Erasmus MC Rotterdam-Sophia Children's Hospital, Rotterdam, Netherlands
12Institute of Child Life and Health, Bristol, United Kingdom
Relapsed/refractory leukemia in childhood carries a grave prognosis. Dasatinib (SPRYCEL®) is a potent oral
kinase inhibitor of BCR-ABL, KIT, and SRC kinases. Dasatinib is approved for adults with Philadelphia
chromosome-positive (Ph(+) CML and ALL, resistant or intolerant to prior imatinib therapy. An investigational
phase I dose-finding study of dasatinib treatment of patients aged 1-21 years with various leukemia subtypes is
currently being conducted in 12 European centers. The aim of the study is to establish a safe and effective
dose for each of the leukemia sub-types. Patients were stratified into three treatment groups - Stratum 1: CML
in chronic phase, resistant or intolerant to imatinib; Stratum 2/3: advanced-phase CML resistant or intolerant to
imatinib, Ph(+) ALL, relapsed/ refractory after imatinib, or Ph(+) AML, ≥ 2nd relapse; Stratum 4: Ph(-) ALL, or Ph
(-) AML in second/subsequent relapse. The starting dose was 60mg/m2 once daily for all strata. Intra-patient
dose escalation was allowed for lack of initial response and dose reductions for toxicity. Current data reflect the
first 41 patients (median age 11 years, range 1-21) treated from March 2006 through May 2008, including eight
in Stratum 1, twelve in Stratum 2/3, and twenty-one in Stratum 4. The patients were heavily pretreated and prior
therapy included chemotherapy (n=35), imatinib (n=20), and stem cell transplant (n=24). Dasatinib was well
tolerated up to the current 120mg/m2 dose. Treatment-related toxicities were mostly mild to moderate in severity
with nausea (34% grade 1/2; 2% grade 3/4) and diarrhea (15% grade 1/2; 0% grade 3/4) occurring most
frequently. In Stratum 4, two dose-limiting toxicities were seen: anaphylaxis 5 hours after the first dose
(60mg/m2) and upper-GI bleed on Day 6 of dasatinib dosing (120mg/m2). Only one of the 41 patients
experienced a malignant/hemorrhagic pleural effusion at 100mg/m2 dose. A maximum tolerated dose has not
been established. PK studies were performed on samples from 32 patients after 60 mg/m2, 80 mg/m2 and 100
mg/m2 dosing. Absorption occurred rapidly (median Tmax 0.75 - 1.0 hour). The area under the curve (AUC)
and maximum concentration (Cmax) proportionately increased with higher dose levels, but the difference was
much greater between 60 and 80 mg/m2 than between 80 and 100 mg/m2. Complete Hematological Response
(CHR) occurred in 75% of patients with CML-CP. Major Hematological Response (MaHR) was achieved in 25%
of patients with advanced CML/Ph(+) and Ph(+) ALL/ AML. Major Cytogenetic Response occurred in 88% of
CML-CP patients and 50% of patients with advanced Ph(+) CML and Ph(+) ALL/ AML. Stratum 4 observations
included a temporary decrease in peripheral blood (PB) blast count in one Ph(-) ALL patient and in PB and
bone marrow (BM) blast counts in two Ph(-) AML patients (one with AML7 and one with Down's syndrome).
Additionally, three Ph(+) ALL patients had a CSF response. These interim data demonstrate a favorable safety
profile for dasatinib. Clear efficacy was seen in patients with CML-CP, and other Ph(+) leukemias. Further
exploration is needed in the Ph(-) leukemias in the pediatric population. Updated data will be presented.
332 Prediction of Cytogenetic Response to Second Generation TKI Therapy in CML Chronic Phase
Patients Who Have Failed Imatinib Therapy and Early Identification of Factors That Influence Survival
Monday, December 8, 2008: 11:15 AM
2009-2011-2022-2024 - West (Moscone Center)
Dragana Milojkovic*, Marco Bua*, Jane F Apperley*, Kasia Kozlowski*, Jamshid Sorori*, Letizia Foroni*, Alistair
Reid*, Jiri Pavlu*, Katy Rezvani*, Francesco Dazzi*, Eduardo Olavarria*, Matthias Klammer*, John M Goldman*
and David Marin
Department of Hematology, Imperial College London, Hammersmith Hospital, London, United Kingdom
Second generation tyrosine kinase inhibitors (2G-TKI) have displaced allogeneic stem cell transplant as the
preferred therapy for patients with CML in chronic phase (CP) who fail imatinib. However a significant proportion
of patients still fail to respond to 2G-TKI and may benefit from alternative therapy (including stem cell
transplant). We have performed univariate and multivariate analyses in our cohort of 80 patients treated with
dasatinib (n=67) or nilotinib (n=13) while still in first CP after imatinib failure in order to identify those patients
who will benefit most with these therapies.
The median age was 50 years and 46% were male; 72 patients were resistant to imatinib (2 primary
haematological resistance, 40 primary cytogenetic, 32 secondary cytogenetic and 25 developed secondary
hematologic resistance) and 8 were intolerant. 20 had developed kinase domain mutations while on imatinib
therapy. 31 and 29 patients received maximal doses of imatinib 600 and 800 mg per day respectively. The
median follow up was 28.3 months (range 6-42).
The 3-year cumulative incidence of CCyR was 52.6%. The multivariate analysis identified four pre-2G-TKI
independent predictive factors for CCyR, namely low Sokal risk score at diagnosis, the best cytogenetic
response obtained on imatinib, G-CSF requirement during imatinib therapy and time from detection of imatinib
failure (as defined by European LeukemiaNet criteria) to onset of second 2G-TKI therapy. Using these factors
we devised a scoring system that could be used to predict the probability of achieving CCyR on 2G-TKI therapy.
The score was calculated by allocating one point when any one of the following four features was present: (1)
intermediate or high Sokal risk group, (2) need of G-CSF support during imatinib therapy, (3) institution of 2G-
TKI more than 18 months after imatinib failure, and (4) failure to achieve a cytogenetic response on imatinib
(≥95% Ph-pos). The 3-year cumulative incidence of CCyR for patients with 0-1 points was 95.6%, with 2 points
50% and with 3-4 points 18.7% (p<0.0001, Figure 1).
For the 80 patients the probability of 3-year survival was 89.6%. We performed a 3-month landmark analysis to
study the relationship between molecular response and subsequent outcome. The 44 patients with a BCR-
ABL1/ABL ratio less than 15% at 3 months had a 3-year overall survival of 100% while the 36 patients with a
ratio >15% had a survival of 77.4% (p=0.003, Figure 2). We performed a multivariate analysis including all
relevant variables defined at the start of 2G-TKI and the 3-month transcript level. The 3-month transcript level
was the only independent predictor for survival.
Similarly we performed a 6-month landmark analysis where we explored the relationship between cytogenetic
response and outcome. Patients who had achieved a MCyR (n=38) or a CCyR (n=32) had a significantly better
survival than those with lower levels of cytogenetic response (100% vs. 79.2% (p=0.006) and 100% vs 82.6
(p=0.02)) respectively. We also performed a multivariate analysis including the variables defined at the initiation
of therapy, the 3-month transcript levels and the cytogenetic response at 6 months. Interestingly the 3-month
molecular response was the only independent variable predicting for survival. Similar results were found for
progression-free survival (data not shown).
We conclude that factors measureable before starting treatment with 2G-TKI may be valuable for predicting
response; molecular responses at 3-months and cytogenetic responses at 6 months provide further information
about the value of continuing treatment with 2G-TKI.
2112 Association of Pleural Effusion and Bleeding in Patients with Chronic Myelogenous Leukemia
Receiving Dasatinib
Sunday, December 7, 2008
Hall A (Moscone Center)
Poster Board II-206
Alfonso Quintas-Cardama, MD1, Hagop M. Kantarjian2*, Susan O'Brien, M.D.3, Farhad Ravandi, MBBS4,
Alessandra Ferrajoli5, Guillermo Garcia-Manero, MD6* and Jorge Cortes, MD2
1Medical Oncology, UT MD Anderson Cancer Center, Houston, TX
2M.D. Anderson Cancer Center, Houston, TX
3Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX
4Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX
5Department of Leukemia, U.T.M.D. Anderson Cancer Center, Houston, TX
6Leukemia, U.T.M.D. Anderson Cancer Center, Houston, TX
BACKGROUND: Dasatinib is an oral potent multikinase inhibitor that has demonstrated high efficacy and safety
in patients (pts) with chronic myelogenous leukemia (CML). Pleural effusion (PE) and bleeding (BL) occur in
some patients receiving dasatinib, frequently resulting in therapy discontinuation. The incidence of the
occurrence of both events in the same pt either concomitantly or sequentially is unknown.
METHODS: We evaluated the incidence of PE and BL either simultaneously or sequentially among 138
consecutive pts (69 female) with CML after failure of imatinib treated at our institution in phase I and II studies of
dasatinib between November 2003 and January 2006.
RESULTS: The median age for the entire cohort was 57 years (range, 15-81), median time on imatinib 164 wks
(range, 21-253). Among 50 pts treated in the phase I study, 23 (46%) were in chronic (CP), 7 (14%) in
accelerated (AP), and 20 (40%) in blastic phase (BP) at the time of dasatinib start, whereas 88 pts received
dasatinib in phase II studies, 43 (49%) in CP, 25 (28%) in AP, and 20 (23%) in BP. Fifteen (11%) pts started
dasatinib at a dose <100 mg, 22 (16%) at 100 mg, 92 (67%) at 140 mg, and 9 (6%) at >140 mg daily. The
median time on dasatinib was 42 wks (range, 4-120). PE occurred in 48 (35%) pts, being grade 3–4 in 23
(17%). The median time to its development was 5 wks (range, 1 to 107). PE occurred in 29% of pts in CP, 50%
in AP, and 33% in BP. Thirty-seven BL episodes were recorded in 32 (23%) pts. Seven (5%) pts had grade 1,
16 (12%) grade 2, 9 (7%) grade 3, and none grade 4-5 BL. The median time to development of BL was 6 weeks
(range, 0.5-38), occurring within the first 3 months of therapy in 22 (69%) pts. BL occurred in 12% of pts in CP,
31% in AP, and 35% in BP. Basic coagulation studies were normal in all pts. Fourteen (37%) BL episodes
occurred with platelets >100x109/L (2 with normal platelet counts). Seventeen (12%) patients had both PE and
BL (2 CP, 5 AP, and 11 BP), representing 36% of those with PE and 53% of those with BL. PE preceded BL in 8
pts while BL preceded PE in 9. The median time from dasatinib start to PE was 28 days (10-230) and to BL was
34 days (3-218). The median time between PE and BL was 17 days (range, 4-216). Six pts had grade 1, 3
grade 2, and 7 grade 3 PE, whereas 4 had grade 1, 10 grade 2, and 3 grade 3 BL (r²=0.03). The median
hemoglobin drop was 2.1 g/dL (range, 1.1-4.5). PE and BL were more frequent among pts treated at daily
doses ≥140 mg compared to those treated at ≤100 mg (100% vs 0%) and among those receiving dasatinib
twice daily compared to once daily (88% vs 12%; p=0.001). Dasatinib was discontinued for a median of 10 days
(median, 0-97) and the dose reduced in 7 pts due to PE. Loop diuretics were given to 10 pts, steroids to 2, and
thoracentesis was required in 4 pts with PE, all of the latter demonstrating exudative features (median 91%
lymphocytes [range, 73-100]). Dasatinib dose was discontinued for a median of 10 days (range, 0-23) and the
dose reduced in 6 pts due to BL. BL types included gastrointestinal in 14 (82%) pts (lower in 11, upper in 3),
gingival in 2, and epistaxis in 1. Nine patients had endoscopic examination demonstrating inflammatory changes
(n=4), gastric ulcer (n=1), rectal ulcer (n=1), no lesion (n=3). Twelve pts required transfusions of packed red
blood cells (PRBCs) and platelets, 3 only platelets, 1 only PRBCs, and 1 none. Dasatinib was terminated due to
PE in 1 and due to BL in 2.
CONCLUSION: PE and BL can occur in a subset of pts with CML during dasatinib therapy, particularly among
pts with AP or BP receiving dasatinib ≥140 mg twice daily. Appropriate clinical monitoring, transient dasatinib
interruption and dose reduction are required to adequately manage these complications.
3242 Dasatinib 100 Mg Once Daily (QD) Maintains Long-Term Efficacy and Minimizes the Occurrence
of Pleural Effusion: An Analysis of 24-Month Data in Patients with Resistance, Suboptimal Response,
or Intolerance to Imatinib (CA180-034)
Monday, December 8, 2008
Hall A (Moscone Center)
Poster Board III-324
Kimmo Porkka, MD, PhD1, H. Jean Khoury2, Ronald Paquette3, Yousif Matloub4*, David Liu4*, Ritwik Sinha4*
and Jorge Cortes5*
1Hematology Research Unit, Biomedicum Helsinki, Helsinki, Finland
2Emory University School of Medicine, Atlanta, GA
3Ronald Reagan UCLA Medical Center, Los Angeles, CA
4Bristol-Myers Squibb, Wallingford, CT
5Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX
Dasatinib (SPRYCEL®) is a potent BCR-ABL inhibitor that is 325-fold more potent than imatinib and 16-fold
more potent than nilotinib against unmutated BCR-ABL in vitro. Pleural effusion in patients during dasatinib
treatment is well described and may have an immune-mediated mechanism, although this remains under
investigation. CA180-034 was a 4-arm randomized, phase III, dose-optimization study in 670 patients (662
treated patients) with chronic myeloid leukemia in chronic phase and resistance, suboptimal response, or
intolerance to prior imatinib. Previously, it was demonstrated that dasatinib 100 mg QD maintained efficacy and
led to fewer key side effects compared with 3 other dosing schedules (140 mg QD, 50 or 70 mg twice daily
[BID]), including significantly fewer pleural effusions. Here, the management and outcomes of 165 patients
randomized to and treated with dasatinib 100 mg QD, with and without pleural effusion, were compared with the
497 patients treated on other dose schedules after a minimum follow-up of 24 mos on CA180-034. Pleural
effusion was graded using standard CTCAE criteria. Overall rates of pleural effusion (all grades) at 12 vs 24
mos were 10% vs 14% for patients treated with dasatinib 100 mg QD, and 16% vs 23%, 21% vs 26%, 20% vs
25% for patients treated with 50 mg BID, 140 mg QD, or 70 mg BID, respectively. In patients receiving 100 mg
QD, rates of pleural effusion by grade at 12 vs 24 mos were: grade 1, 2% vs 1%; grade 2, 6% vs 10%; and
grade 3, 2% vs 2%; no grade 4 events were reported. The median time to development of pleural effusion (of
any grade) was 10.3 mos for 100 mg QD compared with 9.5, 4.9, and 4.5 mos for 50 mg BID, 140 mg QD, and
70 mg BID, respectively. Management for pleural effusion included transient dose interruptions in 12 patients on
the 100 mg QD arm and 71 patients on the other 3 arms combined. Dose reductions for pleural effusion
occurred in 8 patients on the 100 mg QD arm and in 43 patients on the other 3 arms. Medical management of
pleural effusion on the 100 mg QD arm vs the other 3 arms included use of diuretics in 13 patients vs 70
patients, corticosteroids in 6 patients vs 32 patients, and diuretics and/or corticosteroids in 14 patients vs 79
patients. Diagnostic and/or therapeutic thoracentesis was performed in 3 patients on the 100 mg QD arm vs 9
patients in the other 3 arms. The overall major cytogenetic response rate was 64% for 165 patients on the 100
mg QD arm, comprising 70% for those with a pleural effusion and 63% for those without; in the other treatment
arms, rates ranged from 64 to 74% in those with a pleural effusion and from 59 to 61% in those without (Table).
In the 100 mg QD arm, the 24-mo progression free survival rate was 78% in those with a pleural effusion and
80% in those without. In conclusion, pleural effusion is medically manageable; 24-mo data show that dasatinib
100 mg once daily minimizes the risk of pleural effusion and, both in patients with or without a pleural effusion,
maintains long-term efficacy.
Table: 24-month efficacy of dasatinib 100 mg QD
With
pleural effusion
(n=23)
Without
pleural effusion
(n=142)
Major Cytogenetic Response (MCyR) Rate
70%
63%
MCyR Duration at 18 mo
93%
93%
MCyR Duration at 24 mo
70%
90%
Complete Cytogenetic Response (CCyR) Rate
61%
49%
CCyR Duration at 18 mo
93%
95%
CCyR Duration at 24 mo
70%
95%
Progression Free Survival
78%
80%
Overall Survival
89%
91%